This invention relates to a new therapeutic use for levobupivacaine or (S)-1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide, and to new formulations including it.
Racemic bupivacaine is an effective long-acting local anaesthetic, and may be given as an epidural. However, racemic bupivacaine is cardiotoxic, having depressant electrophysiological and mechanical effects on the heart. It should therefore be used with caution in cardiac-compromised patients, and the use of high doses and high concentrations is contraindicated.
In particular, bupivacaine has produced death in a number of patients, including women in childbirth and when used in the Bier""s block technique. Although the incidence of death has been relatively small, the concern has been sufficient to stop the use of 0.75% bupivacaine for obstetrics and the proscribing of bupivacaine for use in Bier""s blocks.
In addition, due to its mode of action, directly on the nervous system, at higher doses, bupivacaine is known to have undesirable central nervous system (CNS) side-effects which, prima facie, are connected to its anaesthetic activity. Indeed, the occurrence of CNS side-effects is one of the major factors limiting the use of this drug in normal clinical practice employing techniques such as local infiltration, nerve block field block, epidural and spinal blocks.
It has been suggested that levobupivacaine is less cardiotoxic than dextrobupivacaine and racemic bupivacaine. See, for example, Vanhoutte et al, Br. J. Pharmacol. 103:1275-1281 (1991), and Denson et al, Regional Anaesthesia 17:311-316 (1992). However, these reports are based on work in vitro, and cannot necessarily be extrapolated to any mammals, and certainly not to humans.
The effective utility of levobupivacaine in man, in vivo, is evidenced for the first time in WO-A-9510276, WO-A-9510277 and Gristwood et al, Exp. Opin. Invest. Drugs 3(11):1209-12 (1994). The latter documents indicate the potential utility of levobupivacaine in obstetrics, in part at least because of reduced CNS side-effects.
Gristwood et al also disclose that bupivacaine has xe2x80x9ca beneficial ratio of sensory to motor blockade. This ratio is particularly important for obstetric use as it affords appropriate sensory block and yet allows women to consciously participate in the childbirthxe2x80x9d. Gristwood et al then report experiments comparing bupivacaine and levobupivacaine, and conclude that a xe2x80x9cpreliminary analysis of the data suggests that in terms of sensory block, levobupivacaine has comparable efficacy to bupivacaine, with the duration of sensory block for 0.25% levobupivacaine being similar to that seen with bupivacaine 0.25%xe2x80x9d.
WO-A-9500148 discloses that ropivacaine salts provide sensory block and xe2x80x9cminimal motor blockadexe2x80x9d. It is suggested that this effect is desirable, because reduced motor blockade (compared to bupivacaine) allows the patient to move, say, legs soon after operation.
There are of course many more major surgical procedures, where profound block is required, the need is for administration of high amounts and volumes of anaesthetic, and where safety is a major consideration. Although racemic bupivacaine is an effective long-acting anaesthetic, large doses may be toxic. Further, particularly when administered as a bolus injection, where there is a real risk of accidentally administering the drug to the wrong site, safety is a critical consideration. For example, there is a risk of intravascular injection, in abdominal surgery, brachial plexus and femoral sciatic nerve blocks.
This invention is based on two surprising observations. The first is that, whereas a large dose of bupivacaine may be fatal in sheep, the same dose of levobupivacaine is not. It is therefore possible to administer much larger amounts of levobupivacaine, safely. Without wishing to be bound by theory, it may be that, because a given dose of levobupivacaine takes longer to reach Tmax than the same dose of racemate, a higher amount of levobupivacaine may safely be administered, that provides anaesthesia.
The second observation is that levobupivacaine exhibits a different pathic handling compared with bupivacaine. This manifests itself as a faster plasma clearance rate within 0-4 hours post-administration. Therefore, for major surgical procedures, where aberrant injection may occur, the risk of harming the patient is reduced due to faster clearance in the problematic phase.
In accordance with the present invention, levobupivacaine is administered as an anaesthetic for major surgery in an amount that could not be used by injection, with confidence, for bupivacaine, i.e. at least 200 mg, often at least 225 mg, and perhaps more than 250 mg, e.g. up to 300 mg. A novel unit dosage or delivery system, e.g. a syrnge, may comprise such an amount of the drug. In terms of the amount of drug administered, this may be at least 3 mg/kg.